The central purpose of the proposed research is to define the roles which drug metabolism and pharmacokinetic factors play in determining the clinical response to certain commonly abused drugs, including the predisposition for compulsive drug use. Attention will be focussed on d-and 1-amphetamine, administered therapeutically to children with minimal brain dysfunction and to adult volunteers; and methadone, given in the course of treatment for chronic heroin addiction. Integrated gas chromatography/mass spectrometry and immunochemical methods will be employed to measure the concentrations of drugs and active metabolites in blood from human subjects, and the clinical response to the drug will be interpreted in terms of these measurements. Concurrent measurements on other body fluids (urine, saliva, sweat) are expected to lead to empirical correlations which may be of greater practical value in routine patient care and drug control programs. Twin studies are proposed to evaluate genetic factors as determinants of both pharmacokinetics and clnical response. Deuterium-labelled variants of amphetamine and methadone will be used to study changes in the single- dose pharmacokinetics of these drugs as tolerance develops in the course of regular administration. An investigation of the metabolism of amphetamine and related compounds will encompass both clinical and experimental studies in order to evaluate both the factors controlling the rate and routes of metabolism and the pharmacological properties of active metabolites. Significant improvements are anticipated in the sensitivity and accuracy of chemical assays and in methods of quantitative evaluation of clinical response to these drugs.